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Describes patterns, overall and according to person- and healthcare-related factors, of discontinuation and re-initiation in people with type 2 diabetes mellitus in New Zealand who are new users of metformin monotherapy. Source: National Library of New Zealand Te Puna Matauranga o Aotearoa, licensed by the Department of Internal Affairs for re-use under the Creative Commons Attribution 3.0 New Zealand Licence.

Forecasting large earthquakes along active faults is of critical importance for seismic hazard assessment. Statistical models of recurrence intervals based on compilations of paleoseismic data provide a forecasting tool. Here we compare five models and use Bayesian model-averaging to produce time-dependent, probabilistic forecasts of large earthquakes along 93 fault segments worldwide. This approach allows better use of the measurement errors associated with paleoseismic records and accounts for the uncertainty around model choice. Our results indicate that although the majority of fault segments (65/93) in the catalogue favour a single best model, 28 benefit from a model-averaging approach. We provide earthquake rupture probabilities for the next 50 years and forecast the occurrence times of the next rupture for all the fault segments. Our findings suggest that there is no universal model for large earthquake recurrence, and an ensemble forecasting approach is desirable when dealing with paleoseismic records with few data points and large measurement errors. There is no universal model for large earthquake recurrence, and an ensemble forecasting approach is desirable when dealing with paleoseismic records with few data points and large measurement errors.

Iron homeostasis plays an essential role in joint health, while iron overload can cause damage and death of cartilage cells. Cardamonin (CAR) is a substance found in the fruit of the chasteberry plant and has anti-inflammatory and anti-tumor activities. We first administered iron dextran (500 mg/kg) intraperitoneally to establish an iron overload mouse model and surgically induced osteoarthritis. The extent of OA and iron deposition were assessed using Micro-ct, Safranin-O/fast green staining, H&E staining, and Prussian Blue 10 weeks later. We administered primary chondrocytes with Ferric Ammonium Citrate (FAC) to evaluate the chondrocyte changes. Chondrocytes were identified in vitro by toluidine blue staining, and chondrocyte viability was evaluated by CCK-8. The rate of apoptosis was determined by Annexin V-FITC/PI assay. The mechanism of action of CAR was verified by adding the SIRT1 inhibitor EX527, and the expression of SIRT1 and MAPK signaling pathways was detected by Western blot. Iron overload also promoted chondrocyte apoptosis, a process that was reversed by CAR. In addition, CAR reduced NLRP3 inflammasome production via the SIRT1-MAPK pathway, and the SIRT1 inhibitor EX527 inhibited the treatment of OA by CAR.CAR inhibited cartilage degeneration induced by iron overload both in vivo and in vitro. Besides, our study showed that iron overload not only inhibited type II collagen expression but also induced MMP expression by catalyzing the generation of NLRP3 inflammasome. Our results suggest that CAR can treat KOA by promoting SIRT1 expression and inhibiting p38MAPK pathway expression to reduce the production of NLRP3 inflammasome vesicles.

BackgroundPatient medication knowledge and health literacy affect patient safety. Taking angiotensin-converting enzyme inhibitors (ACE-i) or angiotensin II receptor blockers (ARBs), with diuretics and non-steroidal anti-inflammatory medications (NSAIDs) is nephrotoxic. Patients may not know of this risk. An eHealth information package was developed to inform patients at risk of taking this combination of medication.ObjectiveTo assess the impact of the eHealth information package on patient knowledge and behaviour.DesignThis was a two-arm, parallel, randomised control trial. A knowledge quiz and NSAID use survey were undertaken at baseline, and repeated after two weeks. The intervention group accessed the information package after completing the baseline assessment. The control group received normal care.Setting and participantsPrimary healthcare patients prescribed an ACE-i or ARB plus a diuretic in Aotearoa New Zealand.InterventionA novel eHealth information package was made available to participants in the intervention group consisting of a downloadable PDF and online education activity. This took approximately 15 min for participants to complete.Primary outcome measuresChange in knowledge scores and in NSAID use between pre-intervention and post-intervention assessment.Secondary outcome measuresSelf-reported patient intentions regarding future NSAID useResultsThe 201 participants who completed the study had high baseline NSAID medication knowledge, which did not substantially change at follow-up. The intervention group had a 0.35 (95% CI: -0.18, 0.88) higher knowledge score than the control group. NSAID use decreased over the study; the intervention group had 62% lower odds of NSAID use at follow-up assessment compared with the control group (OR=0.37, 95% CI: 0.14, 1.03). There was no substantial difference between study groups at follow-up for self-reported action. The information package was considered acceptable and useful.ConclusionThis tailored eHealth information package may reduce NSAID use in patients at increased risk from NSAID-related harm.Trial registration numberAustralian New Zealand Clinical Trial Registry (ACTRN:12622001132730).

Background Despite an overt commitment to equity, health inequities are evident throughout Aotearoa New Zealand. A general practice electronic alert system was developed to notify clinicians about their patient’s risk of harm due to their pre-existing medical conditions or current medication. We aimed to determine whether there were any disparities in clinician action taken on the alert based on patient ethnicity or other demographic factors. Methods Sixty-six New Zealand general practices from throughout New Zealand participated. Data were available for 1611 alerts detected for 1582 patients between 1 and 2018 and 1 July 2019. The primary outcome was whether action was taken following an alert or not. Logistic regression was used to assess if patients of one ethnicity group were more or less likely to have action taken. Potential confounders considered in the analyses include patient age, gender, ethnicity, socio-economic deprivation, number of long term diagnoses and number of long term medications. Results No evidence of a difference was found in the odds of having action taken amongst ethnicity groups, however the estimated odds for Māori and Pasifika patients were lower compared to the European group (Māori OR 0.88, 95 %CI 0.63–1.22; Pasifika OR 0.88, 95 %CI 0.52–1.49). Females had significantly lower odds of having action taken compared to males (OR 0.76, 95 %CI 0.59–0.96). Conclusions This analysis of data arising from a general practice electronic alert system in New Zealand found clinicians typically took action on those alerts. However, clinicians appear to take less action for women and Māori and Pasifika patients. Use of a targeted alert system has the potential to mitigate risk from medication-related harm. Recognising clinician biases may improve the equitability of health care provision.

ObjectivesThe aims of this study were to describe the following: (1) the time to change of therapy in patients with type 2 diabetes who had initiated metformin monotherapy as first-line treatment and (2) the sequence in which subsequent therapeutic regimens were introduced.DesignCohort study.SettingNational study based on linked data from the New Zealand Ministry of Health’s National Collections of health and pharmaceutical dispensing data.ParticipantsPeople with type 2 diabetes mellitus who initiated metformin monotherapy between 1 January 2006 and 30 September 2014 (n=93 874).Primary outcome measuresCumulative incidence curves were plotted to show the time taken to move from one regimen to another, while sunburst plots were used to illustrate the sequence in which regimens were introduced.ResultsAbout 10% and 35% of cohort members had moved to a second regimen 1 year and 5 years, respectively, after initiating metformin monotherapy; the majority received a regimen recommended by New Zealand treatment guidelines (mostly metformin and a sulphonylurea). Of those who started a recommended second regimen, 37% and 67% had moved to a third regimen after 1 and 5 years, respectively; the corresponding proportions for those who started an ‘other’ (not listed as recommended) second regimen were 53% and 75%. Most of those who received a third regimen after a recommended second regimen were dispensed an ‘other’ third regimen. Of those who moved to a third regimen from an ‘other’ second regimen, similar proportions received recommended and ‘other’ third regimens.ConclusionsReal-world type 2 diabetes treatment patterns in New Zealand are complex and not always consistent with guidelines.

BackgroundFollow-up for patients with resected stage IIIA–D melanoma may include computed tomography (CT) or positron emission tomography (PET)/CT imaging to identify distant metastases. The aim of this study was to evaluate the test performance over follow-up time, of structured 6- and 12-monthly follow-up imaging schedules in these patients.MethodsWe conducted a retrospective analysis of consecutive resected stage IIIA–D melanoma patients from Melanoma Institute Australia (2000–2017). Patients were followed until a confirmed diagnosis of distant metastasis, end of follow-up schedule, or death. Test accuracy was evaluated by cross-classifying the results of the test against a composite reference standard of histopathology, cytology, radiologic imaging, and/or clinical follow-up, and then quantified longitudinally using logistic regression models with random effects.ResultsIn total, 1373 imaging tests were performed among 332 patients. Distant metastases were detected in 110 (33%) patients during a median follow-up of 61 months (interquartile range 38–86), and first detected by imaging in 86 (78%) patients. 152 (68%) patients had at least one false-positive result. Sensitivity of the schedule over 5 years was 79% [95% confidence interval (CI) 70–86%] and specificity was 88% (95% CI 86–90%). There was no evidence of a significant difference in test performance over follow-up time or by American Joint Committee on Cancer (AJCC) substage. The positive predictive value ranged between 33 and 48% over follow-up time, reflecting a ratio of 1:2 false-positives per true-positive finding.ConclusionsRegular 6- or 12-monthly surveillance imaging using CT or PET/CT has reasonable and consistent sensitivity and specificity over 5-year follow-up for resected stage IIIA–D melanoma patients. These data are useful when discussing the risks and benefits of long-term follow-up.

IntroductionMobilisation with movement (MWM) is commonly used for treating patients with rotator cuff-related shoulder pain (RCRSP). However, the evidence supporting MWM efficacy for improving shoulder range of motion (ROM) and pain in patients with RCRSP is limited. It is also unclear whether higher volume MWM leads to better clinical outcomes compared with lower volume MWM in patients with RCRSP. The primary aim of this study is to assess the effect of MWM on the angular onset of pain during shoulder abduction in patients with RCRSP.Methods and analysisSixty participants with RCRSP will be randomised to receive either MWM or sham MWM intervention. The primary outcome is the angular onset of pain during shoulder abduction, and secondary outcomes are pain intensity at the angular onset of pain during shoulder abduction, maximum shoulder ROM, pain intensity during maximum shoulder abduction, pressure pain threshold, mechanical temporal summation, global rating of change scale (GROC) and Brief Pain Inventory-Short Form (BPI-SF). The angular onset of pain and the pain intensity at that range will be assessed at baseline, after 1 set and 3 sets of 10 repetitions of MWM or sham MWM. The GROC will be measured immediately after receiving 3 sets of interventions and on day 3 after interventions. The BPI-SF will be measured on days 1, 3, 5 and 7 after interventions. Other secondary outcomes will be assessed at baseline and after 3 sets of interventions. A linear mixed effects model with a random intercept will be used to compare changes in the outcome measures between MWM and sham MWM interventions.Ethics and disseminationThis study has been approved by the University of Otago Ethics Committee (Ref. H21/117). Findings from this study will be disseminated through presentations at international and national conferences and will be submitted for publication in a peer-reviewed journal.Trial registration numberACTRN 12621001723875.

In many scientific studies, the underlying data-generating process is unknown and multiple statistical models are considered to describe it. For example, in a factorial experiment we might consider models involving just main effects, as well as those that include interactions. Model-averaging is a commonly-used statistical technique to allow for model uncertainty in parameter estimation. In the frequentist setting, the model-averaged estimate of a parameter is a weighted mean of the estimates from the individual models, with the weights typically being based on an information criterion, cross-validation, or bootstrapping. One approach to building a model-averaged confidence interval is to use a Wald interval, based on the model-averaged estimate and its standard error. This has been the default method in many application areas, particularly those in the life sciences. The MA-Wald interval, however, assumes that the studentized model-averaged estimate has a normal distribution, which can be far from true in practice due to the random, data-driven model weights. Recently, the model-averaged tail area Wald interval (MATA-Wald) has been proposed as an alternative to the MA-Wald interval, which only assumes that the studentized estimate from each model has a N(0, 1) or t-distribution, when that model is true. This alternative to the MA-Wald interval has been shown to have better coverage in simulation studies. However, when we have a response variable that is skewed, even these relaxed assumptions may not be valid, and use of these intervals might therefore result in poor coverage. We propose a new interval (MATA-SBoot) which uses a parametric bootstrap approach to estimate the distribution of the studentized estimate for each model, when that model is true. This method only requires that the studentized estimate from each model is approximately pivotal, an assumption that will often be true in practice, even for skewed data. We illustrate use of this new interval in the analysis of a three-factor marine global change experiment in which the response variable is assumed to have a lognormal distribution. We also perform a simulation study, based on the example, to compare the lower and upper error rates of this interval with those for existing methods. The results suggest that the MATA-SBoot interval can provide better error rates than existing intervals when we have skewed data, particularly for the upper error rate when the sample size is small.

Background The core intrinsic connectivity networks (core-ICNs), encompassing the default-mode network (DMN), salience network (SN) and central executive network (CEN), have been shown to be dysfunctional in individuals with internalizing disorders (IDs, e.g. major depressive disorder, MDD; generalized anxiety disorder, GAD; social anxiety disorder, SOC). As such, source-localized, closed-loop brain training of electrophysiological signals, also known as standardized low-resolution electromagnetic tomography (sLORETA) neurofeedback (NFB), targeting key cortical nodes within these networks has the potential to reduce symptoms associated with IDs and restore normal core ICN function. We intend to conduct a randomized, double-blind (participant and assessor), sham-controlled, parallel-group (3-arm) trial of sLORETA infraslow (<0.1 Hz) fluctuation neurofeedback (sLORETA ISF-NFB) 3 times per week over 4 weeks in participants ( n =60) with IDs. Our primary objectives will be to examine patient-reported outcomes (PROs) and neurophysiological measures to (1) compare the potential effects of sham ISF-NFB to either genuine 1-region ISF-NFB or genuine 2-region ISF-NFB, and (2) assess for potential associations between changes in PRO scores and modifications of electroencephalographic (EEG) activity/connectivity within/between the trained regions of interest (ROIs). As part of an exploratory analysis, we will investigate the effects of additional training sessions and the potential for the potentiation of the effects over time. Methods We will randomly assign participants who meet the criteria for MDD, GAD, and/or SOC per the MINI (Mini International Neuropsychiatric Interview for DSM-5) to one of three groups: (1) 12 sessions of posterior cingulate cortex (PCC) ISF-NFB up-training ( n =15), (2) 12 sessions of concurrent PCC ISF up-training and dorsal anterior cingulate cortex (dACC) ISF-NFB down-training ( n =15), or (3) 6 sessions of yoked-sham training followed by 6 sessions genuine ISF-NFB ( n =30). Transdiagnostic PROs (Hospital Anxiety and Depression Scale, HADS; Inventory of Depression and Anxiety Symptoms – Second Version, IDAS-II; Multidimensional Emotional Disorder Inventory, MEDI; Intolerance of Uncertainty Scale – Short Form, IUS-12; Repetitive Thinking Questionnaire, RTQ-10) as well as resting-state neurophysiological measures (full-band EEG and ECG) will be collected from all subjects during two baseline sessions (approximately 1 week apart) then at post 6 sessions, post 12 sessions, and follow-up (1 month later). We will employ Bayesian methods in R and advanced source-localisation software (i.e. exact low-resolution brain electromagnetic tomography; eLORETA) in our analysis. Discussion This protocol will outline the rationale and research methodology for a clinical pilot trial of sLORETA ISF-NFB targeting key nodes within the core-ICNs in a female ID population with the primary aims being to assess its potential efficacy via transdiagnostic PROs and relevant neurophysiological measures. Trial registration Our study was prospectively registered with the Australia New Zealand Clinical Trials Registry (ANZCTR; Trial ID: ACTRN12619001428156). Registered on October 15, 2019.